Predicting factors for chronic colonization of Pseudomonas aeruginosa in bronchiectasis.

About 25% of the patients with bronchiectasis are likely to develop a chronic colonization with Pseudomonas aeruginosa. A better understanding of predictors of acquiring Pseudomonas within the patient population may facilitate future focused research. The aim of this retrospective observational study was to investigate predicting factors for P. aeruginosa colonization in patients with bronchiectasis. This was a single-center retrospective cohort study using a bronchiectasis database which consisted of 211 patients with bronchiectasis. Data were collected for demographic details, etiology, spirometry, microbiology data, maintenance medication use, exacerbation frequency, hospital admission rate, and FACED and Bronchiectasis Severity Index (BSI) score. Two hundred eleven patients were identified from our bronchiectasis database. Overall, 25% of the patients (n = 53) had a chronic colonization with P. aeruginosa. Seventeen patients (8%) died in a 5-year follow-up period of whom 7 (41%) had a chronic P. aeruginosa colonization (p > 0.05). After multiple regression analysis, P. aeruginosa-positive patients were significantly associated with an older age (> 55 years) (p = 0.004), the use of hypertonic saline (0.042), and inhalation antibiotics (< 0.001). Furthermore, the presence of PCD (p < 0.001) and post-infectious etiology (p < 0.001) as underlying causes were significantly associated with P. aeruginosa colonization. We observed that independent predictors for P. aeruginosa colonization were age > 55 years, hypertonic saline, and PCD, and post-infectious etiology as underlying causes of bronchiectasis. Since prevention of P. aeruginosa colonization is an important aim in the treatment of bronchiectasis, more attention could be directed to these groups at risk for Pseudomonas colonization.

Patient-reported health outcomes in long-term lung transplantation survivors: A prospective cohort study.

During the last three decades lung transplantation (LTx) has become a proven modality for increasing both survival and health-related quality of life (HRQoL) in patients with various end-stage lung diseases. Most previous studies have reported improved HRQoL shortly after LTx. With regard to long-term effects on HRQoL, however, the evidence is less solid. This prospective cohort study was started with 828 patients who were on the waiting list for LTx. Then, in a longitudinal follow-up, 370 post-LTx patients were evaluated annually for up to 15 years. For all wait-listed and follow-up patients, the following four HRQoL instruments were administered: State-Trait Anxiety Inventory, Zung Self-rating Depression Scale, Nottingham Health Profile, and a visual analogue scale. Cross-sectional and generalized estimating equation (GEE) analysis for repeated measures were performed to assess changes in HRQoL during follow-up. After LTx, patients showed improvement in all HRQoL domains except pain, which remained steady throughout the long-term follow-up. The level of anxiety and depressive symptoms decreased significantly and remained constant. In conclusion, this study showed that HRQoL improves after LTx and tends to remain relatively constant for the entire life span.

CTCA for detection of significant coronary artery disease in routine TAVI work-up : A systematic review and meta-analysis.

Transcatheter aortic valve implantation (TAVI) has evolved to standard treatment of severe aortic stenosis in patients with an intermediate to high surgical risk. Computed tomography coronary angiography (CTCA) could partially replace invasive coronary angiography to diagnose significant coronary artery disease in the work-up for TAVI. A literature search was performed in MEDLINE and EMBASE for papers comparing CTCA and coronary angiography in TAVI candidates. The primary endpoint was the diagnostic accuracy of CTCA, compared to coronary angiography, for detection of significant (>50% diameter stenosis) coronary artery disease, measured as sensitivity, specificity, positive-(PPV) and negative predictive value (NPV). Seven studies were included, with a cumulative sample size of 1,275 patients. The patient-based pooled sensitivity, specificity, PPV and NPV were 95, 65, 71 and 94% respectively. Quality assessment revealed excellent and good quality in terms of applicability and risk of bias respectively, with the main concern being patient selection. In conclusion, on the basis of a significance cut-off value of 50% diameter stenosis, CTCA provides acceptable diagnostic accuracy for the exclusion of coronary artery disease in patients referred for TAVI. Using the routinely performed preoperative computed tomography scans as a gatekeeper for coronary angiography could decrease additional coronary angiographies by 37% in this high-risk and fragile population.

A Multicenter Study on Long-Term Outcomes After Lung Transplantation Comparing Donation After Circulatory Death and Donation After Brain Death.

The implementation of donation after circulatory death category 3 (DCD3) was one of the attempts to reduce the gap between supply and demand of donor lungs. In the Netherlands, the total number of potential lung donors was greatly increased by the availability of DCD3 lungs in addition to the initial standard use of donation after brain death (DBD) lungs. From the three lung transplant centers in the Netherlands, 130 DCD3 recipients were one-to-one nearest neighbor propensity score matched with 130 DBD recipients. The primary end points were primary graft dysfunction (PGD), posttransplant lung function, freedom from chronic lung allograft dysfunction (CLAD), and overall survival. PGD did not differ between the groups. Posttransplant lung function was comparable after bilateral lung transplantation, but seemed worse after DCD3 single lung transplantation. The incidence of CLAD (p = 0.17) nor the freedom from CLAD (p = 0.36) nor the overall survival (p = 0.40) were significantly different between both groups. The presented multicenter results are derived from a national context where one third of the lung transplantations are performed with DCD3 lungs. We conclude that the long-term outcome after lung transplantation with DCD3 donors is similar to that of DBD donors and that DCD3 donation can substantially enlarge the donor pool.

Detection of azole-susceptible and azole-resistant Aspergillus coinfection by cyp51A PCR amplicon melting curve analysis.

BACKGROUND: The AsperGenius® assay is a multiplex real-time PCR test that allows the simultaneous detection of Aspergillus species and identification of the most common mutations in the Aspergillus fumigatus cyp51A gene conferring resistance (TR34/L98H and TR46/T289A/Y121F) by using melting curve analysis. Mixed infections with azole-resistant and susceptible A. fumigatus have rarely been described. METHODS: The AsperGenius® multiplex real-time PCR assay (PathoNostics, Maastricht, the Netherlands) was used on bronchoalveolar lavage (BAL) samples of 91 consecutive patients with a suspected invasive Aspergillus infection at the Erasmus MC University Medical Center, Rotterdam. RESULTS: In three cases the AsperGenius® assay indicated the simultaneous presence of WT and mutant genes (two patients with TR34/L98H mutation and one patient with TR46/T289A/Y121F mutation) and therefore mixed infections with azole-susceptible and -resistant isolates. In one of the three cases, the mixed infection was confirmed by phenotypic antifungal testing of multiple A. fumigatus colonies. CONCLUSIONS: The use of a dedicated A. fumigatus cyp51A resistance PCR allowed the detection of mixed infections with azole-resistant and -susceptible Aspergillus strains. These mixed infections may remain undiagnosed with conventional phenotypic susceptibility testing.

Clinical implementation of a fully automated quantitative perfusion cardiovascular magnetic resonance imaging workflow with a simplified dual-bolus contrast administration scheme.

This study clinically implemented a ready-to-use quantitative perfusion (QP) cardiovascular magnetic resonance (QP CMR) workflow, encompassing a simplified dual-bolus gadolinium-based contrast agent (GBCA) administration scheme and fully automated QP image post-processing. Twenty-five patients with suspected obstructive coronary artery disease (CAD) underwent both adenosine stress perfusion CMR and an invasive coronary angiography or coronary computed tomography angiography. The dual-bolus protocol consisted of a pre-bolus (0.0075 mmol/kg GBCA at 0.5 mmol/ml concentration + 20 ml saline) and a main bolus (0.075 mmol/kg GBCA at 0.5 mmol/ml concentration + 20 ml saline) at an infusion rate of 3 ml/s. The arterial input function curves showed excellent quality. Stress MBF ≤ 1.84 ml/g/min accurately detected obstructive CAD (area under the curve 0.79; 95% Confidence Interval: 0.66 to 0.89). Combined visual assessment of color pixel QP maps and conventional perfusion images yielded a diagnostic accuracy of 84%, sensitivity of 70% and specificity of 93%. The proposed easy-to-use dual-bolus QP CMR workflow provides good image quality and holds promise for high accuracy in diagnosis of obstructive CAD. Implementation of this approach has the potential to serve as an alternative to current methods thus increasing the accessibility to offer high-quality QP CMR imaging by a wide range of CMR laboratories.

The Dutch Dystrophinopathy Database: A National Registry with Standardized Patient and Clinician Reported Real-World Data1.

Background: Duchenne and Becker muscular dystrophy lack curative treatments. Registers can facilitate therapy development, serving as a platform to study epidemiology, assess clinical trial feasibility, identify eligible candidates, collect real-world data, perform post-market surveillance, and collaborate in (inter)national data-driven initiatives. Objective: In addressing these facets, it's crucial to gather high-quality, interchangeable, and reusable data from a representative population. We introduce the Dutch Dystrophinopathy Database (DDD), a national registry for patients with DMD or BMD, and females with pathogenic DMD variants, outlining its design, governance, and use. Methods: The design of DDD is based on a system-independent information model that ensures interoperable and reusable data adhering to international standards. To maximize enrollment, patients can provide consent online and participation is allowed on different levels with contact details and clinical diagnosis as minimal requirement. Participants can opt-in for yearly online questionnaires on disease milestones and medication and to have clinical data stored from visits to one of the national reference centers. Governance involves a general board, advisory board and database management. Results: On November 1, 2023, 742 participants were enrolled. Self-reported data were provided by 291 Duchenne, 122 Becker and 38 female participants. 96% of the participants visiting reference centers consented to store clinical data. Eligible patients were informed about clinical studies through DDD, and multiple data requests have been approved to use coded clinical data for quality control, epidemiology and natural history studies. Conclusion: The Dutch Dystrophinopathy Database captures long-term patient and high-quality standardized clinician reported healthcare data, supporting trial readiness, post-marketing surveillance, and effective data use using a multicenter design that is scalable to other neuromuscular disorders.

Leflunomide as part of the treatment for multidrug-resistant cytomegalovirus disease after lung transplantation: case report and review of the literature.

Treatment of cytomegalovirus (CMV) disease in transplant patients is challenging and, with antiviral resistance to first-line drugs, it remains uncertain which treatment algorithm to follow. Some data suggest that leflunomide, a pyrimidine synthesis inhibitor, can be used to treat resistant CMV infections. We report a 57-year-old CMV immunoglobulin-G (IgG)-seronegative woman, who received a bilateral lung transplant (LuTx) from a CMV IgG-positive donor with CMV primary disease. The CMV strain was genotypically resistant to ganciclovir, foscarnet, and cidofovir. After starting leflunomide as add-on therapy to a multidrug anti-CMV regimen, viral load declined substantially in 2 months without adverse events. This experience is discussed against the background of existing literature on the use of leflunomide as an anti-CMV agent in LuTx recipients.

Immediate impact of COVID-19 on transplant activity in the Netherlands.

The rapid emergence of the COVID-19 pandemic is unprecedented and poses an unparalleled obstacle in the sixty-five year history of organ transplantation. Worldwide, the delivery of transplant care is severely challenged by matters concerning - but not limited to - organ procurement, risk of SARS-CoV-2 transmission, screening strategies of donors and recipients, decisions to postpone or proceed with transplantation, the attributable risk of immunosuppression for COVID-19 and entrenched health care resources and capacity. The transplant community is faced with choosing a lesser of two evils: initiating immunosuppression and potentially accepting detrimental outcome when transplant recipients develop COVID-19 versus postponing transplantation and accepting associated waitlist mortality. Notably, prioritization of health care services for COVID-19 care raises concerns about allocation of resources to deliver care for transplant patients who might otherwise have excellent 1-year and 10-year survival rates. Children and young adults with end-stage organ disease in particular seem more disadvantaged by withholding transplantation because of capacity issues than from medical consequences of SARS-CoV-2. This report details the nationwide response of the Dutch transplant community to these issues and the immediate consequences for transplant activity. Worrisome, there was a significant decrease in organ donation numbers affecting all organ transplant services. In addition, there was a detrimental effect on transplantation numbers in children with end-organ failure. Ongoing efforts focus on mitigation of not only primary but also secondary harm of the pandemic and to find right definitions and momentum to restore the transplant programs.

Down-regulation of the macrophage lineage through interaction with OX2 (CD200).

OX2 (CD200) is a broadly expressed membrane glycoprotein, shown here to be important for regulation of the macrophage lineage. In mice lacking CD200, macrophage lineage cells, including brain microglia, exhibited an activated phenotype and were more numerous. Upon facial nerve transection, damaged CD200-deficient neurons elicited an accelerated microglial response. Lack of CD200 resulted in a more rapid onset of experimental autoimmune encephalomyelitis (EAE). Outside the brain, disruption of CD200-CD200 receptor interaction precipitated susceptibility to collagen-induced arthritis (CIA) in mice normally resistant to this disease. Thus, in diverse tissues OX2 delivers an inhibitory signal for the macrophage lineage.

Chronic norovirus infection among solid organ recipients in a tertiary care hospital, the Netherlands, 2006-2014.

OBJECTIVES: Immunocompromised patients can suffer prolonged norovirus symptoms and virus shedding for many years. Little is known about the prevalence of chronic norovirus infection among solid organ transplant (SOT) recipients. In this study, 2182 SOT recipients were retrospectively tested for chronic norovirus infection. METHODS: The first and last norovirus positive faecal samples of SOT recipients were sequenced to distinguish between persisting infection and re-infection. Patient charts were reviewed to obtain data on health status and treatments. RESULTS: In all, 101 of 2182 (4.6%) recipients were norovirus infected and 23 (22.8%) of these developed chronic norovirus infection. Chronic norovirus infection was found among allogeneic heart, kidney and lung transplant recipients. The median shedding period at the end of the study period was 218 days (range 32-1164 days). CONCLUSIONS: This study shows that chronic norovirus infection is not a rare phenomenon among SOT recipients in a tertiary-care hospital. Further research is needed to study the risk of norovirus transmission to other immunocompromised patients in the hospital and to the general population.

[A rare form of obstructive pulmonary disease]. / Een zeldzame vorm van obstructief longlijden.

BACKGROUND: Lymphangioleiomyomatosis (LAM) is characterised by progressive dyspnoea, spontaneous pneumothorax and cystic pulmonary destruction. The disease may show similarities with emphysema clinically, radiologically and on lung function tests. CASE DESCRIPTION: A 44-year-old woman was referred for lung transplantation because of a 6-year history of dyspnoea and severe obstructive pulmonary function disorder with decreased diffusion capacity. Both her relatively young age and the fact that she had never smoked made us doubt the diagnosis 'COPD'. The pulmonary cysts seen on high-resolution CT (HRCT) suggested LAM. This was confirmed when we revised a pulmonary biopsy that had previously been performed. CONCLUSION: CT investigation should be carried out in patients with severe obstructive pulmonary disease without a risk profile appropriate for COPD. Diffuse, homogenous cysts on CT scan can indicate LAM, particularly in women. Conflict of interest and financial support: none declared.

Allele-specific PCR analysis for detection of the gld Fas-ligand point mutation.

The discovery of a naturally occurring missense point mutation in the gene encoding Fas-ligand (FasL/CD95L) in generalized lymphoproliferative disease (gld) mice has lead to the characterization of FasL as an important mediator of apoptosis. Further analysis of FasL function can be facilitated by crossing the gld mutation onto other mouse-strains, for example those carrying mutations affecting other molecules involved in apoptosis, or disease-prone genetic backgrounds. The success of this is dependent on a quick and reliable screening method. Here we report an allele-specific PCR for detection of the gld mutation. This approach permits the screening of back-crossed F1 progeny within one day, using whole blood samples as a source of genomic DNA. The technique is fast, robust, easily learnt, and unambiguous.

Chemical characterization of a novel peptide from the neuroendocrine light yellow cells of Lymnaea stagnalis.

The neuroendocrine light yellow cells of Lymnaea stagnalis form two clusters of cells in the visceral and right parietal ganglion, respectively. These cells are endogenously bursting neurons whose activities are modified during egg-laying and feeding. Using gel permeation chromatography and reverse phase HPLC we have purified two highly related novel peptides from the light yellow cells. These peptides differ only in length, due to truncation of the amino-terminal aspartic acid residue, which causes a major shift in the charge of the molecule. We conclude that the longer peptide is the immediate precursor of the shorter form. Using whole mount immunocytochemistry, it was confirmed that the light yellow cells produce these peptides.

The effects of age, death period and birth cohort on asthma mortality rates in Australia.

SETTING AND OBJECTIVE: We assessed the relative effects of age, gender, period of death and birth cohort on asthma mortality rates in Australia from 1907 to 2000. DESIGN: Asthma mortality data obtained from the Australian Institute of Health and Welfare were adjusted for changes to the International Classification of Diseases and examined for changes over time and age, period and cohort effects. RESULTS: Age-adjusted period asthma mortality rates indicated epidemics during the mid 1960s and 1980s, predominantly affecting those aged 5-34 years. The main 1960s epidemic coincided with the introduction of high-dose, non-selective beta-sympathomimetic amines. There was a gradual rise in mortality rates in younger age groups, with rates rising from 0.5/100 000 males and 0.9/100 000 females in the 1940s to a peak of 3/100 000 for both sexes in 1966. Fluctuations in mortality rates were influenced by period of death and birth cohort. There was an increased risk of death from asthma with increasing age. CONCLUSION: There was no overall trend in asthma mortality rates in any age group. The 1960s epidemic was probably treatment related. Other increases in mortality occurring despite therapeutic advances may reflect increasing prevalence and highlight the need for ongoing surveillance.

Patients with cystic fibrosis have a high carriage rate of non-toxigenic Clostridium difficile.

Thirty-year-old observations report frequent asymptomatic Clostridium difficile carriage among cystic fibrosis (CF) patients. In this case-control study, we found more carriers among CF patients than controls (47% versus 11%), but most strains carried by CF patients were non-toxigenic (77% versus 17%). Among CF patients, carriers were younger, with more severe pulmonary disease than non-carriers. Strains belonged to multiple PCR-ribotypes, suggesting that these CF patients did not acquire strains from each other.

CD200-CD200R signaling suppresses anti-tumor responses independently of CD200 expression on the tumor.

Expression of CD200, the gene encoding the ligand for the inhibitory immune receptor CD200R, is an independent prognostic factor for various forms of leukemia predicting worse overall survival of the patients. The enhanced expression of CD200 on the tumors implies that anti-tumor responses can be enhanced by blockage of the CD200-CD200R interaction. Indeed, antibody-mediated blockade of the CD200-CD200R inhibitory axis is currently evaluated in clinical tests to boost immune responses against CD200-expressing tumors. Here, we show that mice lacking CD200, the exclusive ligand for CD200R, are resistant to chemical skin carcinogenesis. Importantly, CD200R controls tumor outgrowth independently of CD200 expression by the tumor cells themselves. Furthermore, Cd200(-/-) mice do not become tolerant to intranasally administered antigens, suggesting that tumor rejection is normally suppressed through CD200-induced immune tolerance. Decreased tumor outgrowth is accompanied by increased expression of the proinflammatory cytokines interleukin (IL)-1ß and IL-6 by the lymph node (LN) dendritic cells. During carcinogenesis, skin-draining LNs of Cd200(-/-) mice contain increased numbers of IL-17-producing FoxP3(+) cells, which preferentially home to the tumors. Thus, the CD200-CD200R axis induces tolerance to external and tumor antigens and influences the T-regulatory/Th17 cell ratio. We demonstrate for the first time that the absence of CD200R signaling inhibits outgrowth of an endogenous tumor irrespective of CD200 expression by the tumor cells. This important paradigm shift leads to a much broader applicability of CD200-blockade in the treatment of tumors.

LFRFamides: a novel family of parasitation-induced -RFamide neuropeptides that inhibit the activity of neuroendocrine cells in Lymnaea stagnalis.

We report the characterization of a cDNA encoding a novel -RFamide neuropeptide precursor that is up-regulated during parasitation in the snail Lymnaea stagnalis. Processing of this precursor yields five structurally related neuropeptides, all but one ending with the C-terminal sequence -LFRFamide, as was confirmed by direct mass spectrometry of brain tissue. The LFRFamide gene is expressed in a small cluster of neurons in each buccal ganglion, three small clusters in each cerebral ganglion, and one cluster in each lateral lobe of the cerebral ganglia. Application of two of the LFRFamide peptides to neuroendocrine cells that control either growth and metabolism or reproduction induced similar hyperpolarizing K+-currents, and inhibited electrical activity. We conclude that up-regulation of inhibitory LFRFamide neuropeptides during parasitation probably reflects an evolutionary adaptation that allows endoparasites to suppress host metabolism and reproduction in order to fully exploit host energy recourses.

[Age dependence of the P2 latency of visually evoked cortical responses to checkerboard pattern reversal (author's transl)]. / Altersabhängigkeit der P2 -Latenzzeiten schachbrettmusterevozierter Potentiale.

The age dependence of the P2 latency of visually evoked cortical responses to checkerboard pattern reversal was examined in 60 healthy individuals of between 10 and 69 years of age. Separate examination of the right and left eye yielded no statistically significant difference in P2 latency. A certain age dependence of P2 latency was discovered inasmuch as healthy individuals under 15 years and over 65 are--with high statistically significance--apt to show longer P2 latency than healthy individuals in the remaining life span.

Application of a diode-array detector in capillary electrophoresis.

In the last decade diode-array detection has proved to be extremely useful in high performance liquid chromatography in recording UV-visible spectra directly and on-line in the column effluent. In capillary electrophoresis (CE) only fast-scanning detectors with long scan times (up to 2 s) are commercially available. A home-made CE instrument with a diode-array detector (DAD) was built and compared with a commercial fast-scanning detector. It is shown that the fast-scanning detector is advantageous when less than eight wavelengths are monitored. Due to the high data collection rate the DAD is superior if high resolution UV-visible spectra are acquired or if several spectra of a narrow peak (usual peak width in CE below 5 s) are needed for peak purity control. It is shown that DAD detection can help to develop separation methods, to identify peaks according to their UV-visible spectra, and to check peak purity.